U.S. Pat. No. 5,733,914 (which is incorporated herein by reference) describes a series of pyrido[2,3-d]pyrimidines that inhibit protein tyrosine kinase mediated cellular proliferation. The compounds are anti-angiogenic agents, and as such are useful for treating cancer, particularly leukemia and breast cancer. The U.S. Pat. No. 5,733,914 patent teaches that a particularly preferred group of compounds are substituted at the 2-position with an arylamino group, and that the aryl moiety can be a pyridyl group. 2-(4-Pyridyl)amino-pyrido[2,3-d]pyrimidines appear to be a preferred group of compounds because of their metabolic stability and tyrosine kinase selectivity. One such compound, namely 2-(pyridin-4-ylamino)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one, is currently being studied as a possible clinical candidate for treating cancer.
According to the synthetic process described in U.S. Pat. No. 5,733,914, an alkylsulfanyl (a sulfide) group could not be readily displaced by an amine such as a 4-aminopyridine, whereas an alkylsulfinyl group (a sulfoxide) could be so displaced. Accordingly, the 2-alkylsulfanyl pyridopyrimidines first had to be oxidized to provide the corresponding sulfoxide, namely a 2-alkylsulfinyl pyridopyrimidine. The use of such oxidants is not only dangerous on large scale and often causes over-oxidation, but also is very costly, given that the oxidants are expensive and the process adds another chemical step and isolation. This invention avoids these expenses.
Because these compounds are commercially viable anticancer agents, the need exists for a synthetic process that affords the desired compound in high purity and satisfactory yields. This invention provides a commercially viable one-step process for making such pyridylamino-pyrido[2,3-d]pyrimidines in high yield and high purity.